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Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.

ABSTRACT: The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-? mediated degradation of ?-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises ?-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.

SUBMITTER: Mangolini M

PROVIDER: S-EPMC6155045 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.

Mangolini Maurizio M Götte Frederik F Moore Andrew A Ammon Tim T Oelsner Madlen M Lutzny-Geier Gloria G Klein-Hitpass Ludger L Williamson James C JC Lehner Paul J PJ Dürig Jan J Möllmann Michael M Rásó-Barnett Lívia L Hughes Katherine K Santoro Antonella A Méndez-Ferrer Simón S Oostendorp Robert A J RAJ Zimber-Strobl Ursula U Peschel Christian C Hodson Daniel J DJ Schmidt-Supprian Marc M Ringshausen Ingo I

Nature communications 20180921 1

The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradati ...[more]

PMID: 30242258

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Project description:BackgroundThe Wnt/?-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/?-catenin pathway inhibitor genes - CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 - in the cell lines EHEB and MEC-1 as well as patient samples.MethodsQuantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and ?-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models.ResultsFor 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/?-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of ?-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with ?-catenin and thus demonstrating its epigenetically regulated inhibition effect.ConclusionsThe results suggest an epigenetic silencing mechanism of the Wnt/?-catenin pathway inhibitor genes in CLL. Hypermethylation and silencing of functionally related genes may not be completely stochastic but result from the tumour epigenome reprogramming orchestrated by Polycomb-group repressive complexes. The data are of interest in the context of epigenetic-based therapy.

Dataset Information

Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.

Publications

Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.

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